Naproxen is a common name for D-2-(6-methoxy-2-naphthyl)propionic acid which is known to be a non-steroidal agent having anti-inflammatory, analgesic and antipyretic activity. South African Patent No. 67/07597 issued to Syntex as assignee in 1968 disclosed that 2-(napth-2'-yl) acetic and propionic acid derivatives were useful for therapeutic purposes. Since that time, the D-enantiomer of 2-(6-methoxy-2-naphthyl)propionic acid has proven particularly useful as a therapeutic agent and several synthesis processes have been developed in the art.
The propionic acid derivative, 2-(6-methoxy-2-naphthyl)propionic acid, exists as two enantiomers (D- and L-), also known as optical isomers, and the D-enantiomer sold as "naproxen" is known to be much more therapeutically potent than its L- ccunterpart. Therefore, during some phase of synthesis the D- and L- enantiomers are separated to provide the naproxen product. The prior art suggests two general schemes for preparing D-2-(6-methoxy-2-naphthyl)propionic acid. The first scheme encompasses several 2-stage methods wherein the first stage is organic synthesis of a racemic, (DL-) 2-(6-methoxy-2-naphthyl)propionic acid and the second stage comprises isolating the therapeutically effective D-enantiomer. Several methods for resolution of the optical isomers of 2-(6-methoxy-2-naphthyl)propionic acid are known in the art. For example, U.S. Pat. No. 3,637,767 issued to Syntex as assignee discloses reacting the racemic product with an optically active base to form a D-enantiomer salt. The salt is crystallized, separated and then recovered as D-2-(6-methoxy-2-naphthyl)propionic acid by acidification. U.S. Pat. No. 4,800,162 to Matson utilizes multi-phase and extractive enzyme membrane bioreactors as a means to produce substantiall purified optically active compounds from mixtures of active and inactive isomers.
A second general scheme for preparing naproxen focuses on asymmetric organic synthesis of the D-2-(6-methoxy-2-naphthyl)propionic acid product. These methods utilize optically pure starting materials or reagents, or may comprise stereo-selective synthesis steps. For example, European Patent No. 0,163,338 to Blaschim teaches using optically pure chiral reagents for direct stereo-specific synthesis.
The present invention is directed to providing an alternative process for the organic synthesis of racemic (DL-) 2-(6-methoxy-2-naphthyl)propionic acid, and also to providing intermediates for use in stereo-selective processes. It is known to synthesize racemic 2-(6-methoxy-2-naphthyl)propionic acid by various routes using 2-methoxynaphthalene as a starting material. A substituent is introduced at the C-6 position on the naphthalene nucleus via Freidel-Crafts acylation to yield a ketone intermediate 2-acetyl-6-methoxynaphthalene. [See U.S. Pat. No. 3,994,968 to Syntex as assignee]. The acylation may require halogenation or other methods to block substitution at other positions on the compound.
Several routes to the propionic acid derivative are known which utilize the ketone intermediate 2-acetyl-6-methoxynaphthalene heretofore described. For example, an early method known as the "Willgerodt/Methyl Iodide" process first prepares an acetic acid derivative from the ketone intermediate in the presence of morpholine and sulfur and then completes a series of steps including esterifying, methylating, and hydrolyzing the compound to produce (DL-)2-(6-methoxy-2-naphthyl)propionic acid. [E.g. U.S. Pat. No. 3,994,968 issued to Syntex as assignee; U.S. Pat. No. 3,958,012 to Fried et al.]. Although this method has utility, the percent conversion from the ketone intermediate to the acid derivative product is relatively low (20% to 30%), whereas the cost of raw materials and reagents is relatively high.
Another method known in the art converts the ketone group of 2-acetyl-6-methoxynaphthalene to a 2-substituted propylene oxide using a trimethylsulfonium iodide reagent, followed by conversion to a propylene aldehyde and oxidation to the 2-substituted propionic acid. [U.S. Pat. Nos. 3,994,968 and 3,637,767 to Syntex as assignee]. The yields are higher (approximately 30% to 40%) than that observed with the Willgerodt/Methyl Iodide process, however the yields are still too low to justify the high cost of the trimethylsulfonium iodide reagent and raw materials.
Other known routes include hydrocyanation of the carbonyl group of the ketone intermediate 2-acetyl-6-methoxynaphthalene followed by conversion to a 2-substituted propionic acid through a series of steps. This method has about a 30% to 40% conversion as well and calls for expensive reagents such as triethylaluminum. Other process steps for the preparation of 2-(6-methoxy-2-naphthyl)propionic acid are known which utilize intermediates derived from the acylated 2-methoxynaphthalene as starting or intermediate materials. [E.g. U.S. Pat. No. 4,414,405 to Giorano; U.S. Pat. No. 4,620,031 to Uggeri; U.S. Pat. No. 3,651,148 to Nelson et al.].
Although the above conventional routes have utility, using 2-methoxynaphthalene as a starting material (or its precursor 2-naphthol) is expensive, partially due to industry demand, to the high cost of reagents, and to disposal of waste products. There is need for a process that utilizes inexpensive materials and results in a high yield of product.
It is therefore a primary object of this invention to provide a process for the organic synthesis of 2-(6-methoxy -2 -naphthyl)propionic acid that utilizes readily available and inexpensive starting material of fixed isomeric purity.
It is a further object of this invention to provide a process for the organic synthesis of 2-(6-methoxy-2-naphthyl)propionic acid that utilizes 2,6-diisopropylnaphthalene as a starter material.
Another object of this invention is to provide a process for the organic synthesis of 2-(6-methoxy-2-naphthyl)propionic acid that does not require Friedel-Crafts acylation.
It is still a further object of this invention to provide a process for the organic synthesis of 2-(6-methoxy-2-naphthyl)propionic acid having a high percent of conversion of 2,6-diisopropylnaphthalene to 2-(6-methoxy-2-naphthyl)propionic acid.
A further object of this invention is to provide a process for the organic synthesis of 2-(6-methoxy-2-naphthyl)propionic acid whereby the unreacted products and reaction reagents are recyclable.
It is another object of the present invention to provide a process for the organic synthesis of 2-(6-methoxy-2-naphthy)propionic acid that eliminates waste associated with the use of some conventional method reagents.
It is still another object of the present invention to provide a process for the organic synthesis of 2-(6-methoxy-2-naphthyl)propionic acid whereby the reagents are inexpensive and some of the needed reactants are provided by the process.
Another object of the present invention is to provide ga process for the organic synthesis of 2-(6-methoxy-2-naphthyl)propionic acid wherein several steps can be run continuously, thereby lowering capital costs and increasing throughout.
It is also a object of the present invention to provide a process for the organic synthesis of 2-(6-methoxy-2-naphthyl)propionic acid that can be used in combination with other processes to asymmetrically prepare D-2-(6-methoxy-2-naphthyl)propionic acid.
A further object of the present invention is to provide a process for the organic synthesis of 2-(6-methoxy-2-naphthyl)propionic acid which produces intermediates applicable to other synthesis processes.
These and other objects are achieved by a novel process for preparing 2-(6-methoxy-2-naphthyl)propionic acid and the intermediates therefor, a preferred route exemplified as follows: ##STR1##
Formula I is 2,6-diisopropylnaphthalene; Formula II is 2-(1-hydroperoxy-1-methylethyl)-6-(1-methylethyl)naphthalene; Formula III is 2-hydroxy-6-(1-methylethyl)naphthalene; Formula IV is 2-methoxy-6-isopropylnaphthalene; Formula V is 2-methoxy-6-(1-hydroperoxy-1-methylethyl)naphthalene; Formula VI is 2-methoxy-6-isopropenylnaphthalene; Formula VII 2-(6-methoxy-2-naphthyl)-1-propylene oxide; Formula VIII is 2-methoxy-6-(1-hydroxy-1-methylethyl)naphthalene; Formula IX is 2-(6-methoxy-2-naphthyl)propionaldehyde; and Formula X is 2-(6-methoxy-2-naphthyl)propionic acid.